TRANSCRIPTIONAL ACTIVATION OF THE UROKINASE RECEPTOR GENE BY ENDOTHELIN-1

Using an immortalized human glomerular epithelial cell line (E71 A1), we studied the effect of endothelin-1 (ET-1), a potent vasoconstrictor peptide, on the synthesis of urokinase type plasminogen activator (u-PA) and its receptor (u-PAR). The results show that ET-1 had no effect on u-PA synthesis but induced an increase in u-PAR number (2.8±0.6×104 vs 1.2±0.5×104 sites per cell, p < 0.001) without change in receptor affinity (280±80 pM vs 250±50 pM, NS), maximal effect being observed at 10-7M . Time course shows that a plateau was reached after a 24 hour incubation. ET-1 induced-increase in binding capacity was abolished by cycloheximide. ET-1 also induced an increase in u-PAR mRNA level, which was completely blocked by α-amanitin (5 μg/ml). Cycloheximide (1 μg/ml) alone induced an increase in u-PAR mRNA level and this effect was enhanced when cycloheximide was combined with ET-1. Our data show that ET-1 can induce an increase in membrane expression of u-PAR through activation of the transcription of the u-PAR gene and de novo protein synthesis. © 1992 Academic Press, Inc.